Phthalimides: developments in synthesis and functionalization

Phthalimides, an important class of biologically active N-heterocycles, are not only found in pharmaceuticals, natural products, agrochemicals, polymers, and dyes, but also serve as building blocks in organic transformations. Many synthetic methods, including metal catalysis and metal-free systems, have been developed to prepare functionalized phthalimides. In this review, we describe the developments in the synthesis and functionalization of phthalimides over the past two decades.

Thus, the synthesis and functionalization of these valuable frameworks is highly important.Since the rst application of phthalimide in organic synthesis by S. Gabriel in 1887, 27 the use of phthalimide derivatives as versatile precursors in organic transformations have achieved great interest. 28,29Various synthetic methods have been documented for the preparation of phthalimides, including metal-catalyzed aminocarbonylation cyclizations of ortho-dihaloarenes or ortho-haloarenes, the amidation of phthalic acid/anhydride by primary amines and annulations involving maleimide.However, in many of these synthetic strategies, CO gas is used as a carbonyl precursor, and due to its many disadvantages, such as toxicity, lack of odor; ammability and issues related to storage, handling, transportation and safety, research efforts are undertaken to search for less toxic, more accessible and easy to handle carbonyl precursors.
In addition to the preparation of these scaffolds, the functionalization of phthalimides, especially N-arylation, has received widespread attention. 30In this context, recently, remarkable approaches to the functionalization reactions of phthalimides through C-N bond formation via C(sp 2 )-H/ C(sp 3 )-H bond cleavage have been developed under metal or non-metal catalysis.
Owing to the high importance of phthalimide derivatives, in the current review, we describe the development in the synthesis of phthalimides and N-functionalizations of these scaffolds.In this regard, the review is divided into two main categories: the synthesis and the functionalization of phthalimides.The rst section is classied on the basis of the transition metal catalyzed reaction and metal-free synthetic method, and the next part is devoted to the N-arylation and N-Scheme 1 Representative examples of biologically active molecules containing phthalimide scaffold.

Synthesis of phthalimides
2.1.Transition metal-catalyzed synthesis of phthalimides 2.1.1.Ni-catalyzed synthesis of phthalimides.The rst example of coupling of aliphatic and aromatic isocyanates (2)  with 1,3-iodoesters and ortho-iodobenzenes (1) catalyzed by a nickel catalyst was reported by Cheng and co-workers in 2005 (Scheme 2). 31The reaction was inuenced by the electronic nature of the functional groups on the aryl ring of isocyanate, where an electron-donating substituent enhanced the reactivity but an electron-withdrawing substituent did not.Moreover, alkylisocyanates resulted in higher yields compared to arylisocyanates.In addition, a siloxane group on isocyanate could give a 92% yield of the product.As shown in Scheme 3, the reaction involved the reduction of Ni(II) to Ni(0) by zinc powder to insert into the C-I bond through oxidative addition.The obtained intermediate A then underwent the isocyanate insertion to form intermediate B. Intramolecular imidation furnished product 3 along with the release of an ester group and the regeneration of Ni(II).
2.1.2.Cu-catalyzed synthesis of phthalimides.Xie and coworkers developed an efficient Cu/TBHP catalysis system for the construction of phthalimide derivatives 5 through the oxidation of arene-fused cyclic amines 4 (Scheme 4). 32Various Cu catalysts, such as Cu(OAc) 2 , CuCl 2 , CuCl, CuBr, and CuI led to phthalimide products in good yields and among them, the best result was obtained using CuCl as a catalyst.This synthetic method was also used for the synthesis of a building block in organic solar cells and organic eld-effect transistors, namely thieno [3,4-c]pyrrole-4,6-dione (TPD) 5.This reaction involved the cyclization of bispropargylamines 6 to 6-dihydrothieno [3,4c]pyrroles 7 in the presence of zirconocene, followed by the oxidation under the Cu/TBHP catalysis system to form TPD 8.
N-Substituted phthalimides can be synthesized from 1indanones 9 and aryl/alkyl amines 10 in the presence of CuO 2 as a catalyst (Scheme 5). 33 In 2021, a nano-Cu 2 O catalyst was employed by Chen et al. for the assembly of phthalimides (Scheme 6). 34A wide variety of amines 10, 2-halobenzoic acids 12 and TMSCN 11 were treated in the presence of a nanocatalyst in water as a solvent to obtain the N-substituted phthalimides 5.In addition to phthalimides, a series of malimides 14 was also constructed in this method through the cyclization of b-iodoacrylic acids 13.It was found that Cu(I) nanocatalyst is involved in all reaction steps, including cyanation, cyclization and hydrolysis.The mechanistic investigations indicated that the two intermediates A and C are involved and TMSCN is necessary in the reaction.The reaction mechanism started with the generation of 2-cyanobenzoic acid A via the cyanation of 2-iodobenzoic acid 12 with TMSCN 11 under copper catalysis, followed by an intramolecular nucleophilic addition toward intermediate B. Aer that, the hydrolysis of B to phthalic anhydride C, and subsequent amine attack led to product 5 along with the elimination of a H 2 O molecule (Scheme 7).This strategy has the advantages of low catalytic loading, the use of green solvent H 2 O, and no need for CO, ligand, or an additive in the reaction.
Chen and Bao prepared phthalimides 5 and unsubstituted cyclic imides 18 from copper-catalyzed cyclization of diaryliodonium salts 15 with cyanoesters 16 or 17 (Scheme 8). 35In general, the reaction involved the initial interaction between CuBr and diaryliodonium salts 15 to form Cu(III) complex B and aryl iodide A. The coordination of cyanoester 16 to the Cu center resulted in intermediate C, which was further converted to a more reactive intermediate D through the elimination of Cu(I).This intermediate can proceed in two possible pathways.In path I, an intramolecular nucleophilic addition led to intermediate E, followed by the N-acylation to yield the isophthalimide F. Finally, phthalimide 5 was furnished via a 1,3-(O-N) acyl transfer rearrangement process.Another possible pathway that can be considered for this transformation is via the amide formation (intermediate G in path II).However, with a control experiment that treated substrate 15 with an amide reagent, no phthalimide product was formed, ruling out this pathway (Scheme 9).
2.1.3.Co-catalyzed synthesis of phthalimides.In 2018, a cobalt-catalyzed synthesis of N-pyridyl phthalimide derivatives 20 via the carbonylation of benzoyl hydrazides was described by the Zhai group (Scheme 10). 36By studying the deuterium labeling experiment of substrate 19 and the H/D exchange (CD 3 OD/CH 3 OH) experiment, the authors indicated that the C-H bond cleavage is not the rate-determining step, and this step is reversible.The removal of the pyridyl moiety could be easily carried out in the presence of RANEY® and H 2 .According to the mechanism, two pathways were proposed for the formation of cobaltacycle B. In path I, the coordination of hydrazide 19 with Co(II), followed by the C-H bond activation led to the Co(III) complex B in the presence of Ag 2 CO 3 .While in path II, rst, the oxidation of Co(II) to Co(III) was promoted by Ag 2 CO 3 , which then underwent C-H activation with 19.Aerward, B underwent the insertion of CO to obtain the 6membered cobaltacycle C, followed by reductive elimination to yield phthalimide 20 with the regeneration of the Co(I) species.The oxidation of Co(I) to the active Co(II) species was carried out by Ag 2 CO 3 (Scheme 11).
2.1.4.Pd-catalyzed synthesis of phthalimides.In 2005, Alterman and his team were able to synthesize phthalides and phthalimide through palladium-catalyzed carbonylation of aryl bromides using Mo(CO) 6 as a CO source. 37The reaction mechanism was not reported in this work and the scope of phthalimide was limited to one derivative.In 2010, Alper and Cao developed a novel three-component reaction, involving orthodihaloarene, 21 amine 10 and gaseous carbon monoxide to construct N-substituted phthalimide derivatives 5 (Scheme 12). 38A palladium complex was used as a catalyst and the reaction was carried out in ionic liquid as a green solvent.To enhance the product yield of phthalimide rather than 2-halo benzamide byproduct, 1 atmosphere of CO should be used.A similar dicarbonylation reaction for the assembly of phthalimide scaffolds was reported in the same year. 39In this work, aryl/alkyl/heteroaryl amines reacted smoothly with ortho-dihalobenzene, ortho-iodobenzoinc acid and ortho-iodobenzoate under 90 psi of CO gas.
Interestingly, in the same year, a CO-free strategy was proposed for the synthesis of N-substituted phthalimides 5 from amides 23, and ortho-dihaloaryles 21, ortho-iodobenzoinc acid 12 or ortho-iodobenzoate 1 (Scheme 13). 40In this regard, Bhanage and co-workers applied palladium acetate as a catalyst and POCl 3 as a Lewis acid in this double carbonylation.The authors proposed a possible reaction mechanism, which was initiated by the oxidative insertion of Pd into the C-X bond to obtain the aryl palladium intermediate 1, followed by the attack on the imminium salt A to form B. For o-dihaloarenes, this process was carried out for both the ortho-halo groups.Aerward, b-hydride elimination in B afforded intermediate C for the case of ortho-dihaloarenes, while for ortho-halo acid and ortho-halobenzoate D was the obtained intermediate.In the next stage, C led to E through the attack of the amide lone pair on the carbonyl group of the other o-amide, followed by intramolecular cyclization to form product 5.This product was furnished from F via the attack of lone pair the amide on acid or ester carbonyl group and subsequent intramolecular cyclization (Scheme 14).A polymer-supported palladium-N-heterocyclic carbine was introduced for the synthesis of N-substituted phthalimides 5 from ortho-halobenzoic acid 12, aryl/alkyl amines 10 and CO (Scheme 15). 41In this method, Bhanage and co-workers did not use POCl 3 in the reaction and the decarboxylative cyclization of ortho-halobenzoic acid was carried out in the presence of a heterogeneous and reusable catalyst, which could be recovered for several cycles.In addition to ortho-halobenzoic acids, methyl ortho-iodobenzoate also gave the desired product in good yields (70-80%).In this synthetic method, 14.5 psi of CO was required.
In 2015, Bhanage and his team synthesized a series of Nsubstituted phthalimides using a palladium catalyst (Scheme 16). 42In this context, they treated N-substituted 2-iodobenzamides 25 with phenyl formate in the presence of a palladium catalyst to obtain phthalimides 5 under solvent-free conditions.Whereas, the reaction of benzamides 26 with phenyl formate 24 needed solvent to proceed.The use of phenyl formate made this method unnecessary for the CO gaseous.A catalytic cycle was proposed for this transformation, which involved the oxidative addition of Pd(0) to 2-iodobenzamide 25 to obtain the arylpalladium intermediate A. In the meantime, phenyl formate was decomposed into CO under heat, which then reacted with A to form the acylpalladium intermediate B. In this stage, two possible pathways were considered for the production of phthalimide 5 from B. In path I, a phenoxycarbonylation of B, followed by an intramolecular annulation gave 5. While, a nucleophilic intramolecular attack occurred in B to form 5. Furthermore, the researchers showed that the use of this palladium catalytic system for the reaction of 2-iodoanilide 7 with phenyl formate 24 led to the benzoxazinone synthesis (Scheme 17).In the same year, a palladium-catalyzed synthesis of phthalimides was reported from 2-OTS benzamides and CO as a carbonyl source. 43Another palladium catalysis synthetic method for the assembly of phthalimides was reported by Sekar and co-workers. 44In this method, 2-iodobenzamides were treated with CO gaseous under a binaphthyl-supported palladium (Pd-BNP) catalyst as a heterogeneous and reusable catalyst.Also, the reaction of 2-bromobenzamide with oxirane as a CO source can lead to phthalimide in the presence of Pd/C. 45n 2017, a three-component reaction was extended for the preparation of phthalimides under palladium catalysis (Scheme 18). 46In this regard, bromobenzonitrile 31, isonitrile 32, and aromatic amines 10 were treated in the presence of Pd(OAc) In 2018, a new palladium catalyst was applied for the synthesis of phthalimide frameworks 5 (Scheme 20). 47The palladium catalyst with an imidazole ligand can act as an efficient catalyst in the reaction of ortho-diiodobenzenes 21 or methyl 2-iodobenzoate 1 with amines under a CO atmosphere.The presence of imidazole ligand can promote the catalytic activity and the reaction efficiency.It is noteworthy that a low amount of this catalyst could catalyze the aminocarbonylation of 1,2-diiodoarenes at a shorter reaction time compared to other palladium catalysts (6-36 h), and also in lower pressure of CO than other related reports.Another palladium catalyst was used for the aminocarbonylation of aryl aldehydes 34 by amines 10 and CO gas (Scheme 21). 48In this method, the imine and H 2 O generated from the condensation of amine and aldehyde, acted as a directing group and a nucleophile, respectively.As shown in Scheme 22, the mechanism started with the imine-assisted C-H activation process to obtain intermediate A. further oxidized in the presence of CuO and O 2 to yield product 5.The generated Pd(0) could be reoxidized to the active Pd(II) catalyst.In another report, palladium acetate was used in the reaction of 2-iodobenzamides and formic acid to form the phthalimide derivatives. 49Formic acid served as a carbonyl source in this reaction.
In 2020, Das et al. used a new polystyrene-supported palladium (Pd@PS) nanoparticle (NPs) catalyst for the assembly of phthalimides 5 (Scheme 23). 50In their method, 1,2-dihalobenzene 21, or 2-halobenzoates 1 reacted with ammonium carbamate 35 and oxalic acid 36.The protocol has the advantages of a heterogeneous catalyst, the use of oxalic acid instead of CO gaseous, and the use of ammonium carbamate as an amine synthon.In another work, this group treated 2-iodobenzamides and 2-iodobenzylanilines 25 with oxalic acid 36 to achieve a wide spectrum of phthalimides 5 and isoindolinones 40 (Scheme 24). 51polystyrene supported-palladium (Pd@PS) nanoparticles were used for this transformation, which could be recovered and reused for six cycles without signicant loss of catalytic activity.Briey, the oxidative addition of Pd@PS to the C-I bond of 25 generated the Pd complex A. Meantime, oxalic acid decomposed under thermal conditions into CO, which coordinated with A to form the acyl Pd complex B. Intramolecular nucleophilic attack of the N-atom on the Pd center afforded the cyclized intermediate C, followed by reductive elimination to yield product 5 and regenerate Pd@PS catalyst to restart the next cycle (Scheme 25).
In 2024, another group reported the preparation of phthalimides 5 and amides 42 from 2-iodobenzamide 25 and iodobenzene 41, respectively catalyzed by PdCl(PPh 3 ) 2 SnCl 3 (Scheme 26). 52In this method, a CO balloon was used as the carbonyl source and the nal products were obtained in moderate to high yields.It is noteworthy that the combination of Pd with Sn as a catalyst was necessary for the reaction to proceed.In  In the same year, a novel class of phthalimide scaffolds was synthesized through palladium-catalyzed double C-H activation/annulation of alkynyl-oxime ethers 43 using maleimide 44 (Scheme 27). 53By changing some parameters in the reaction, such as the copper oxidant and the solvent, two different kinds of products were obtained under palladium catalysis.Where 1.0 equivalent of Cu(OAc) 2 and 2.0 equivalents of K 2 CO 3 were used in DCE as a solvent, C-H activation of alkynyl-oxime ether by Pd(II) and subsequent annulation resulted in the phthalimide product.This reaction proceeded through the formation of the alkenyl-palladium intermediate A by the 5-endo-dig cyclization of oxime ether 43 in the presence of Pd(II), followed by regioselective 1,4-Pd migration to the C-H bond of another aryl ring.While 1.0 equivalent of CuCl 2 , and 1.0 equivalents of K 2 CO 3 as well as THF as a solvent were needed for the synthesis of the maleimide product 46.In this case, aer the C-H activation process leading to intermediate A, the coordination and insertion of maleimide 43 gave product 46.
2.1.5.Rh-catalyzed synthesis of phthalimides.In 2014, the Li research group developed a rhodium catalysis system for the construction of phthalimides 5 from the cyclization reaction between benzoic acids 47 and isocyanate 2 (Scheme 28). 54The reaction involved ortho-C-H activation of benzoic acids and subsequent amination.Not only aryl isocyanates, but also alkyl isocyanates reacted smoothly to afford N-substituted phthalimides.According to the mechanism in Scheme 29, a ligand exchange was carried out between NaOAc and [Cp*RhCl 2 ] 2 to obtain the active species A, which was then coordinated to the carboxylic oxygen to render the rhodium benzoate B. Direct C-H bond activation in B afforded the rhodacycle C, which underwent the coordination with isocyanate 2, followed by the insertion into the Rh-C bond to form the rhodium alkoxide E. Intramolecular dehydration of E gave product 5 and regenerated the active catalyst A. By the kinetic isotope effect (KIE) experiment, the authors indicated that the C-H activation is the rate-determining step and proceed through the electrophilic aromatic substitution (S E Ar) mechanism.
In  The deuterium labelling experiment using deuterated ethanol revealed that the C-H activation step is reversible and not rate-limiting step due to the kinetic isotope effect experiment.
2.1.6.Ru-catalyzed synthesis of phthalimides.Ackermann and De Sarkar in 2014 explored C-H activation of benzamides with isocyanates in the presence of a ruthenium(II) complex (Scheme 32). 56In this Ru-catalyzed C-H activation, the reaction of substituted benzamides 51 with isocyanate 2 led to phthalimides 5, while the use of furan or pyrrole substrates 52 produced the uncyclized amides 53 as the nal products.Mechanistic studies revealed a reversible C-H bond metalation of amide 51 by Ru(II) complex, followed by the coordination of isocyanate 2 to form intermediate C. A migratory insertion in C gave intermediate D. Aerward, D underwent a protodemethylation process to render diamide 5, or direct imidation to deliver phthalimide 5 along with the regeneration of the cationic ruthenium species A (Scheme 33).

Metal-free synthesis of phthalimides
8][59][60][61] Compared to transition metal catalysts, these methods offer a greener appeal.][64][65] In 2004, Li and co-workers reported the synthesis of phthalimide 5 from the amidation of phthalic anhydride 54 by amine 10 under metal-free conditions (Scheme 34). 66The products were obtained in excellent yields with a trace amount of the uncyclized byproduct 55.In 2013, an imidazole catalyst was utilized for the synthesis of phthalimides 57 from 1,2-benzenedinitriles 54 (Scheme 35). 67The reaction was carried out through double hydration of 1,2-benzenedinitriles, followed by intramolecular cyclization.Imidazole can catalyze the reaction of N,N 0 -dialkyl-or N,N 0 -diaryl-urease series 59 with phthalic acid 58 towards N-substituted phthalimides 5 (Scheme 36). 68Imidazole can activate the carbonyl moiety in phthalic acid for further attack of urea.Phthalimides were obtained in moderate to high chemical yields.
In 2022, Anandhan and co-workers were able to control the radical cyclization cascade for the preparation of 3hydroxyisoindolin-1-ones 61, phthalimides 5 and isoquinoline-1,3,4(2H)-triones 62 (Scheme 37). 69 Chung and co-workers disclosed an oxidative approach for the synthesis of phthalimides via an unusual ring formation in 1,4-dimethoxyphthalazines (Scheme 43). 72For this purpose, an electrophilic chlorinating reagent, such as trichloroisocyanuric acid (TCICA) was used to chlorinate the N-atom of substrate 64.The conversion of the 6-membered ring substrate to the 5-  A novel library of highly functionalized phthalimides 67 was constructed by Deng and co-workers in 2023 (Scheme 45). 73In this strategy, maleimides 44 and acetophenones 66 were used as starting materials and H 2 O acted as an oxygen source.By the H 2 O 18 isotope labelling experiment, the authors could prove that the oxygen of phenolic in the product originated from

N-Arylation
In 2005, N-arylation of several cyclic imides, including naphthalimide 69, maleimide 44, phthalimide 57, and perylenebis(imide) 74 was performed by Wasielewski and coworkers (Scheme 47). 74A wide range of arylboronic esters were compatible in this work.However, dibenzamide 75 and phenyl boron pinacolate 68 did not participate in this arylation.Aer a while, an active copper was used for N-arylation of various amines, amides, b-lactams and imides under microwave irradiation (Scheme 48). 75Phthalimide 5 and maleimide 44 as the imide substrates led to the N-arylated products in high yields.This method has advantages of short reaction time, high yields and the performance of the reaction in aqueous media or under solvent-free conditions.However, the products were obtained in lower yields in a solvent-free system.
In 2010, KF supported by alumina was utilized for N-functionalization of phthalimides 57 (Scheme 49). 76Strong basicity of KF-Al 2 O 3 can efficiently abstract the N-H imide and increase the nucleophilicity of the nitrogen of phthalimide.Various electrophilic reagents, such as allyl halides, secondary alkyl halides, epichlorohydrin, and methyl iodide well participated in the reaction with phthalimides.Among them, primary electrophiles gave partially higher yields compared to secondary electrophiles possibly due to the steric hindrance.In addition, the non-formation of the elimination byproduct indicates the efficiency and chemoselectivity of this transformation.In 2013, transamidation of NH-phthalimides 57 with amines 10 was extended in the presence of sulfated tungstate as a heterogeneous catalyst (Scheme 50). 77In addition to NH-phthalimides, various amides, such as formamide, benzamide, and acetamide led to the corresponding N-substituted amides.
In 2014, Sanford and co-workers employed an iridium photocatalyst for the of N-acyloxyphthalimides by using aromatic and heretoaromatic precursors (Scheme 51). 78reliminary mechanistic investigation revealed the necessity of visible light for the reaction progress and the involvement of a radical route.According to the mechanism in Scheme 52, photo-excited state IrðppyÞ * 3 was generated from ground state Ir(ppy) 3 under visible light irradiation, followed by a single electron transfer to 79, resulting in the N-centered phthalimidyl The arylation of phthalimides 57 using triaryl bismuth 82 can be carried out in the presence of Cu(OAc) 2 as a catalyst (Scheme 56). 81The steric hindrance of the triaryl bismuth has an important role in the transmetallation from bismuth to copper.Ortho-methyl triphenyl bismuth had a negative effect on the reaction.In addition, the nature of functional groups on the aryl ring of triaryl bismuth has a signicant effect on the reaction progress.For example, the halo substituents at the aryl ring decreased the reactivity, whereas electron-donating groups, such as Me and OMe have a positive effect on the reaction.The mechanism was initiated by the conversion of Cu(II) to Cu(I), which was then incorporated in the oxidative addition with this method, a series of aryldiazonium tetrauoroborate was used as an arylating reagent, which could be decomposed to an aryl radical and N 2 under Cu catalysis.
Nemoto et al. developed a visible light strategy for the preparation of the N-arylated phthalimides 5 (Scheme 58). 83The arylation proceeded through the photolysis of Niodophthalimide intermediate A, which was generated from the iodination of phthalimide by PhI(OAc) 2 /I 2 .According to the DFT calculations, the photolysis of N-iodophthalimide A in the presence of visible light proceeded via transition state T1.In this TS, the length of the N-I bond in the triplet excited state is longer than the ground state, which showed the easy cleavage of the N-I bond in the triplet excited state.The formation of the Narylated phthalimidyl radical occurred with a low activation energy (11.3 kcal mol −1 ).Finally, the aromatization of the radical intermediate C to N-aryl phthalimide 5 was carried out thermodynamically (Scheme 59).This protocol provided a metal-, and photocatalyst-free synthesis of a wide range of phthalimide derivatives up to excellent yield.

N-Alkenylation
In 2021, functionalization of phthalimide 57 and maleimide 44 through a three-component reaction, including phthalimide/ maleimide 57, 44, dialkyl acetylene dicarboxylates 84 and trialkyl/aryl phosphites 83 was carried out under catalyst-free conditions (Scheme 60). 84 Very recently, Dömling and co-workers explored a metal-free methodology for the functionalization of phthalimides using isocyanides and ketones as coupling partners (Scheme 65). 87he method involved a Passerini reaction, in which NH of phthalimide acted as an acid precursor and enabled activation of the carbonyl moiety of ketone 66.The activated carbonyl underwent the attack of isocyanide 94.Meantime, the N-atom of

Conclusions
As shown in this review, various transition metals can catalyze the synthesis of phthalimides from ortho-dihaloarenes, orthohaloacids/esters/benzamides, cyclic ketones, cyclic amines, maleimides, etc.Also, phthalimides can be obtained from phthalic anhydrides, aldehydes, phthalic acids, ortho-formylbenzoic acids, ortho-dicyanoarenes, cyclic ketones and benzamides under metal-free reactions.Although reactions using metal catalysts resulted in higher efficiency, the use of organocatalysts and visible light irradiation displayed a reliable and promising system for phthalimide synthesis.
Nevertheless signicant achievements in the synthesis of phthalimide cores, the construction of highly functionalized phthalimides is still of great challenge for the synthetic community.
Other issues in this eld are the use of CO gas and noble metal catalysts in the phthalimide synthesis that are better replaced with other green synthetic methods.Finding safe and sustainable C1 precursors and developments in catalyst-free photochemical, and electrochemical systems seems to be a good alternative in this eld.Also, the use of chiral organocatalysts in the synthesis of enantioselective phthalimides is still underexplored.
In addition, the acidic nature of the imide moiety in phthalimide allows it to be incorporated into hydrogen bonding interaction, leading to good solubility in polar solvents.The formation of stable complexes through the chelation with metals makes it an invaluable starting material or intermediate for the preparation of various types of bioactive molecules, such as alkaloids and pharmacophores.So far, it has been observed that phthalimide and its analogues have shown similar or even better biological effects than known pharmaceutical products, so their biological activity is one of the important topics of biomedical research.
The reaction involved the C-C bond cleavage and the C-N bond formation access to phthalimide, where O 2 acted as a green oxygen source.DFT calculations revealed the possibility of both a-C-H as well as b-C-H activation in the reaction.The formation of 1,2-indandione A occurred under Cu catalysis in the presence of O 2 , which by further oxidation gave 1,2,3-indantrione B. The extrusion of CO 2 from B led to ortho-phthalic anhydride, which reacted with amine 10 to form imide 5.
2 and Et 3 N to produce a series of N-substituted phthalimides 5.By changing the bromobenzonitrile substrate (when n = 0) to 2-(2bromophenyl)acetonitrile (when n = 1) and the replacement of NEt 3 with PPh 3 , this multi-component reaction led to 1Hindenes as the nal products.Two catalytic cycles were proposed for these transformations (Scheme 19).In the path I, oxidative addition of 31 to Pd(0) produced the aryl palladium species A, which was subjected to cyclopalladation to form the four-membered palladium cycle B.The subsequent double insertion of isocyanide 32 into the Pd-C bond resulted in intermediate C, which underwent reductive elimination to render intermediate D, followed by the isomerization towards intermediate E. Finally, an amine exchange between 10 and E delivered product 33.In path II, the oxidative addition of 31 0 with L 2 Pd(0) led to F, followed by the insertion of 32 to render G.This intermediate then reacted with 10 to form intermediate H. Subsequent reductive elimination of H, followed by the nucleophilic attack of amidine to the nitrile generated intermediate J, which hydrolyzed to product 5 under acidic conditions.

aminoquinoline benzamides 48
with diethyl dicarbonate 49 (Scheme 30).55The procedure was performed in the absence ofCO and additive and diethyl dicarbonate served as a carbonyl synthon.As shown in Scheme 31, the oxidative addition of Rh to 49 gave rhodium ethoxide B. Then, C-H bond activation of 48 by B occurred to obtain the ve-membered rhodacycle C. At this stage, two possible pathways were suggested by the authors.In path I, C underwent reductive elimination to obtain ortho-(ethoxycarbonyl) benzamide F with concomitant regeneration of the Rh catalyst.Aerward, product 50 was furnished through intramolecular N-nucleophilic attack.While, in path II, C underwent a CO de-insertion and subsequent C(aryl)-Rh insertion to yield acyl rhodium intermediate E, followed by reductive elimination to deliver product 50 and an EtOH molecule.
membered ring product was initiated by the rst N-chlorination of 64 by TCICA, followed by the second N-chlorination to form the cationic intermediate A. Then, an intramolecular C-N bond formation in A led to the strained bicyclic intermediate B, which was readily opened by a nucleophile in the reaction mixture to obtain a more stable intermediate C. Next, C was transformed into intermediate D and then into product 65 with the loss of an activated methyl group (Scheme 44).DFT calculations conrmed the formation of transition states and the tentative mechanism.
H 2 O.As outlined in Scheme 46, the reaction mechanism involved the initial self-condensation of acetophenones 66 in the presence of Lewis acid.Then, dypnone A was transformed to iododypnone B in the presence of I 2 .The nucleophilic attack of H 2 O to B yielded intermediate C, which underwent an H-shi to generate intermediate D. Aer that, (4 + 2)-cycloaddition between D and 44 gave intermediate E, which dehydrated and oxidized to form product 67.Further dehydration of F could also lead to byproduct 67 0 .
Scheme 57 Possible mechanism for Cu-catalyzed N-arylation of phthalimides with triaryl bismuth.

Scheme 62
Scheme 62 Possible mechanism for the visible light-mediated reaction of N-phenylpiperidine and phthalimide.
phthalimide interacted with the C-atom of isocyanide to form the cyclic intermediate A. Finally, alcohol 95 was formed by a proton shi from phthalimide to the oxygen of ketone.Various phthalimide derivatives as well as maleimide could be served as an acid reactant in this Passerini reaction.Moreover, a further transformation of phthalimide 95 in the presence of hydrazine led to amidine 96.